The proposed studies will continue to investigate the influence of hypertonic mannitol on cardiac muscle. The experiments that are proposed are the logical and necessary extensions of work that has been in progress for the past 3 years and which has been supported by a National Institutes of Health grant. Specifically, the research proposed for the future will utilize isolated, isometrically contracting cat papillary muscles; isolated in vitro buffer perfused vascular smooth muscle preparations; isolated, blood perfused canine hearts; anesthetized, open-chest dog preparations and unsedated, closed-chest intact dog models to continue the investigation of mannitol's influence on the heart. The experiments will attempt to identify the mechanism of mannitol's ability to reduce vascular resistance and increase coronary blood flow in isolated smooth muscle vascular preparations. Studies will also be done to identify the influence that the component parts of the ischemic process, acidosis and hypoxia, have on mannitol's inotropic effect and ability to increase coronary blood flow using both isolated papillary muscle and anesthetized and awake, unsedated dog preparations. Comparative studies directed at determining whether mannitol exerts a different inotropic effect in isolated cardiac muscle from different species will be obtained by studying isolated rat and cat papillary muscles. Additional studies will also be done to try to determine the precise role of cell swelling in the development of myocardial necrosis and the influence of myocardial cell swelling on coronary blood flow in the heart and whether mannitol is capable of preventing any negative effect cell swelling might have on either the progression to necrosis or any detrimental effect it might have to reduce coronary blood flow. Finally, studies will be done in the awake, unsedated dog to determine the effect of mannitol on organ histology and function in animals continuously given mannitol for several days. The experiments conducted over the last 3 years have brought us to the point where it should be possible to answer these remaining important questions in a 3-year period of time.